Pathogenesis Of Reflux Esophagitis Research Articles

Pathogenesis of Reflux Esophagitis and Progress of Chinese Medicine Intervention

Pathogenesis of Reflux Esophagitis and Progress of Chinese Medicine Intervention

Neutrophils, eosinophils, and intraepithelial lymphocytes in the squamous esophagus in subjects with and without gastroesophageal reflux symptoms

Whilst intraepithelial lymphocytes (IELs) are considered normal within the distal esophageal mucosa, they have an increasingly recognised role in the pathogenesis of reflux esophagitis, and IEL quantification establishes the diagnosis of lymphocytic esophagitis. Knowledge regarding the upper limit of a normal IEL count in health is lacking. We studied 117 non-healthcare seeking adult volunteers from a random community sample (the Kalixanda study) with esophageal biopsies 2 cm above the gastroesophageal junction. Subjects were divided into four groups based on the presence or absence of gastro-esophageal reflux symptoms and/or esophagitis on endoscopy. Asymptomatic subjects with no endoscopic esophagitis were selected as controls, and the cell counts in this group were used to define the upper limit of normal of IELs, eosinophils and neutrophils. The entire sample was used to identify independent predictors of increased cellular counts by logistic regression analysis. None of the healthy controls had an IEL count of more than three per five high power fields (HPF), and therefore this was considered as the upper limit of normal; no controls had eosinophils or neutrophils in esophageal biopsies. Independent predictors of an elevated IEL count were spongiosis on histology (OR 11.17, 95% CI 3.32-37.58, P < 0.01) and current smoking (OR 4.84, 95% CI 1.13-2.71, P = 0.03). A receiver operating characteristics analysis concluded that a threshold of 3 IELs/5HPFs performs best in predicting reflux symptoms when a normal esophageal mucosa is visualized on endoscopy (sensitivity = 100.0%, specificity = 35.2%). The healthy esophageal mucosa does not contain more than three IELs per five HPF in the distal esophagus.

Increased Reflux Esophagitis after Helicobacter pylori Eradication Therapy in Cases Undergoing Endoscopic Submucosal Dissection for Early Gastric Cancer

Simple SummaryHelicobacter pylori infection is associated with the development of gastric cancer. Reflux esophagitis may occur in the postoperative period of patients undergoing surgical therapy for gastric cancer. The role of eradication therapy of Helicobacter pylori in reflux esophagitis is controversial. Here, we evaluated the occurrence of reflux esophagitis before and after Helicobacter pylori eradication in patients having endoscopic submucosal resection for early gastric cancer. Reflux esophagitis before and after eradication therapy was evaluated during the follow-up. While reflux esophagitis incidence increased from 3.1% to 18.8% in the successful eradication group, no case of reflux esophagitis was observed in the failed eradication group. There was a significant correlation between successful Helicobacter pylori eradication rate and reflux esophagitis development. This study demonstrates that a successful Helicobacter pylori eradication therapy is a risk factor for newly developed reflux esophagitis in patients having endoscopic submucosal dissection for early gastric cancer.Background: The role of Helicobacter pylori in the pathogenesis of reflux esophagitis is controversial. This study investigated the frequency of reflux esophagitis before and after H. pylori eradication in patients having endoscopic submucosal dissection for early gastric cancer. Methods: This study included 160 patients that fulfilled the study’s criteria. Endoscopy was performed before and after H. pylori eradication, and reflux esophagitis was evaluated during the follow-up period. Results: Seropositivity for H. pylori in patients with early gastric cancer was 68.8%, 101 of them received eradication therapy. During the follow-up period, the incidence of reflux esophagitis increased from 3.1% to 18.8% in the successful eradication group but no case of reflux esophagitis was observed in the failed eradication group. The univariate and multivariate analyses showed a significant correlation between successful H. pylori eradication rate and the development of reflux esophagitis. Conclusions: This study demonstrated that a successful H. pylori eradication therapy is a risk factor for newly developed reflux esophagitis in patients with endoscopic submucosal dissection for early gastric cancer.

Key molecules involved in the Th17/Treg balance are associated with the pathogenesis of reflux esophagitis and Barrett's esophagus.

Reflux esophagitis (RE) impairs the squamous epithelium that normally lines the esophagus, and contributes to the replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus (BE), which is considered as a precursor of esophageal adenocarcinoma. This study aimed to investigate the changes in the balance of Th17/Treg and the related key molecules in the pathogenesis of RE and BE and evaluate the diagnostic and predictive value of the molecules in patients with these diseases. The proportions of Th17 and Treg in RE and BE patients were estimated using flow cytometric analysis. Key molecules involving in the Th17/Treg balance, including RORγt, Foxp3, IL-17, IL-6, IL-10, and TGF-β, were measured using quantitative real-time PCR (qRT-PCR) and ELISA analyses. The diagnostic and predictive value of the Th17/Treg ratio and its key regulators was evaluated using a receiver operating characteristic assay (ROC). In addition, the Spearman correlation analysis explored the relationship between the Th17/Treg ratio and the clinical characteristics. An increased ratio of Th17/Treg was observed in RE and BE compared with the normal controls, and the proportion of Th17/Treg in BE was further increased compared with RE patients. Moreover, the expression levels of RORγt, IL-17, IL-6, and TGF-β were elevated, while the levels of Foxp3 and IL-10 were reduced in patients when compared to the controls. Compared with the RE groups, the levels of IL-17 were significantly higher in BE patients, while the Foxp3 levels were significant decreased. In addition, the Th17/Treg ratio also showed high diagnostic significance and considerable predictive value for the clinical outcomes in patients with RE and BE. The balance of Th17/Treg was impaired in patients with RE and BE. Th17/Treg may be involved in the development of both RE and BE through regulating the release of inflammatory cytokines, but the concrete mechanisms maybe different in the two diseases. The imbalance of Th17/Treg ratio and the related key molecules had a certain clinical diagnosis and prediction potential for RE and BE.

Sa1105 - P-Akt/Akt Pathways in the Crural Diaphragm are Involved in the Pathogenesis of Reflux Esophagitis in Humans — a Preliminary Report

Sa1105 - P-Akt/Akt Pathways in the Crural Diaphragm are Involved in the Pathogenesis of Reflux Esophagitis in Humans — a Preliminary Report

Sa1104 - P-Akt/Akt Pathways in the Crural Diaphragm are Involved in the Pathogenesis of Reflux Esophagitis in Rats

Sa1104 - P-Akt/Akt Pathways in the Crural Diaphragm are Involved in the Pathogenesis of Reflux Esophagitis in Rats

Reflux esophagitis and its role in the pathogenesis of Barrett's metaplasia.

Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus, the precursor of esophageal adenocarcinoma. Therefore, to prevent the development of Barrett's metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2α, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury. In some individuals, reflux esophagitis heals with Barrett's metaplasia. A number of possibilities exist for the origin of the progenitor cells that give rise to this intestinal metaplasia including those of the esophagus, the proximal stomach, or the bone marrow. However, intestinal cells are not normally found in the esophagus, the stomach, or the bone marrow. Thus, the development of Barrett's intestinal metaplasia must involve some molecular reprogramming of key developmental transcription factors within the progenitor cell, a process termed transcommitment, which may be initiated by the noxious components of the gastric refluxate. This review will highlight recent studies on the pathogenesis of reflux esophagitis and on reflux-related molecular reprogramming of esophageal squamous epithelial cells in the pathogenesis of Barrett's metaplasia.

Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes.

The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid. To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis. Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015. PPIs stopped for 2 weeks. Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity). At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P = .005] and 2 weeks [P = .002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; Δ, 16.2% [95% CI, 4.4%-26.5%], P = .005), mucosal impedance decreased (mean: 2671.3 Ω at baseline to 1508.4 Ω at 2 weeks; Δ, 1162.9 Ω [95% CI, 629.9-1695.9], P = .001), and all patients had evidence of esophagitis. In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury. clinicaltrials.gov Identifier: NCT01733810.

500 The Induction of Pathological Acid Reflux With Acute Reflux Esophagitis in Humans Is Associated With T Lymphocyte-Predominant Inflammation of the Esophageal Mucosa: A New Paradigm for the Pathogenesis of Reflux Esophagitis

Introduction: Reflux esophagitis (RE) traditionally has been assumed to start when acid and pepsin destroy esophageal squamous cells at the luminal surface, inducing an acute, granulocyte-predominant inflammatory response. However, recent studies in animal RE models have challenged this traditional notion, suggesting that refluxed gastric juice does not destroy squamous cells directly, but instead stimulates them to secrete chemokines, which attract lymphocytes that mediate tissue damage. Patients typically have months to years of GERD symptoms before seeking medical attention, and so the early histologic changes of RE have not been evaluated prospectively in humans. To elucidate those changes, we induced acute RE by discontinuing PPIs in patients with healed RE. Methods: Patients with a prior endoscopy showing LA grade C RE were treated with PPIs BID for at least 1 month before a baseline endoscopy to document healing. PPIs then were stopped and endoscopy repeated 1 and 2 weeks later. At each endoscopy, 4 biopsies were taken from nonulcerated mucosa in the distal esophagus for histology and immunohistochemical staining for lymphocyte markers (CD3, CD20). Esophageal pH monitoring and GERD-HRQL symptom scoring were performed at baseline and 2 weeks. Biopsies were scored for type and degree of inflammation, for basal and papillary hyperplasia, and for spongiosis (dilated intercellular spaces) on a scale of 0 to 3. Results: 9 patients (8 men; mean age 67 years) had mean esophageal acid exposure (total % time pH<4) that increased from 6.6% at baseline to 28.4% at 2 weeks (p=.002), and mean GERD-HRQL scores that increased from 8.3 to 13.4 (p= .03). All patients developed endoscopic RE by 2 weeks (2 LA-A, 3 LA-B, 4 LA-C). Lymphocytes were by far the predominant type of inflammatory cell. Lymphocytes, basal and papillary hyperplasia, and spongiosis increased significantly from baseline to week 1, but not from week 1 to 2 (see Table). Lymphocytes were almost exclusively CD3+T cells, and found predominantly in peripapillary areas. There were few eosinophils in any biopsy at any time point. Neutrophils were also few in number and generally found only in association with micro-erosions at weeks 1 and 2; 4 of the 9 patients had no neutrophils in any biopsy at any time. Conclusions: In patients with severe RE healed by PPI therapy, stopping PPIs for 2 weeks causes a profound increase in acid reflux with acute RE that is characterized histologically by infiltration of the esophageal mucosa with T lymphocytes. Neutrophils and eosinophils do not appear to play an important role. The finding that acute RE in humans is a form of lymphocytic esophagitis supports the new paradigm for RE pathogenesis suggested by animal studies in which reflux does not destroy esophageal squamous cells directly, but rather stimulates them to secrete chemokines that attract lymphocytes.

Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis.

IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE). IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription1 (STAT1) siRNA were used. IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA. Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.

Tu1123 Acid and Bile Salts Activate Hypoxia Inducible Factor (HIF)-2α and Increase Transcription of HIF-Target PRO-Inflammatory Cytokines in Esophageal Squamous Cell Lines: A Potential Mechanism for the Pathogenesis of Reflux Esophagitis

Tu1123 Acid and Bile Salts Activate Hypoxia Inducible Factor (HIF)-2α and Increase Transcription of HIF-Target PRO-Inflammatory Cytokines in Esophageal Squamous Cell Lines: A Potential Mechanism for the Pathogenesis of Reflux Esophagitis

Mo1087 Esophagoprotective Activity of Angiotensin-(1-7) in Rat Model of Acute Reflux Esophagitis. Role of Sensory Neuropetides and Proinflammatory Cytokines

The pathogenesis of reflux esophagitis results from an imbalance between aggressive factors damaging the esophagus and the natural antireflux barriers. The local renin-angiotensin system (RAS) exists in esophageal mucosa, however, its contribution to the mechanism of esophageal integrity has not been clarified. Angiotensin-(1-7) (Ang-(1-7)) which is an important component of the RAS, was recently implicated in gastroprotection but its effect on damage induced by reflux esophagitis (RE) has not been explored. We evaluated the possible protective effect of Ang-(1-7) against mucosal lesions induced by the acute RE induced in anesthetized rats by ligating of the pylorus and the limiting ridge (transitional region between the forestomach and the corpus of stomach). Rats were pretreated 30 min before induction of RE either with 1) vehicle (saline), 2) Ang-(1-7) (5 75 μg/kg i.p.), 3) Ang-(1-7) (50 μg/ kg i.p.) without and with A 779 (2.5 mg/kg i.p.), a selective antagonist of Ang-(1-7) Mas receptor, 4) Ang 1-7 (50 μg/kg i.p.) without and with capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves, and 5) antisecretory treatment with PPI inhibitor, pantoprazole (10 mg/kg i.g.). Four hrs after induction of esophagitis, the damage was graded with mucosal lesion index (LI) from 0-6, the esophageal blood flow (EBF) was determined by H2-gas clearance technique and the RT-PCR expression and plasma levels of proinflammatory cytokines IL-1β and TNF-α was determined by ELISA. The esophageal LI and wet weight in esophagitis were significantly higher and the EBF was decreased by 35% as compared with the intact mucosa Pretreatment with Ang-(1-7) which in intact rats increased the EBF by 25% without any damage and alteration in plasma IL-1β and TNF-α levels, almost completely prevented, similarly as pantoprazole, the esophageal mucosal injury and significantly increased EBF by about 18% as compared to that in vehicle-controls with RE. The esophagoprotective effects and the rise in EBF induced by Ang-(1-7) were completely abolished by A779. Capsaicin denervation which by itself failed to affect the esophageal lesions, also reduced the esophagoprotective and hyperemic effects of Ang-(1-7) and both protection and hyperemia were restored by co-treatment with CGRP (10 μg/kg s.c.). Ang(1-7) significantly decreased the RE-induced increase in mRNA expression and plasma IL1β and TNF-α levels and these effects were also abolished by pretreatment with A779 and capsaicin-sensory denervation. We conclude that Ang-(1-7), a potent vasodilatatory member of angiotensin family peptides, exhibits esophagoprotection against the esophageal damage induced by reflux esophagitis via mechanism involving activation of Mas receptor, the stimulation of sensory nerves releasing of vasodilatatory CGRP and the suppression of expression and release of IL-1β and TNF-α.

Dietary Antioxidant and Mineral Intake in Humans Is Associated with Reduced Risk of Esophageal Adenocarcinoma but Not Reflux Esophagitis or Barrett’s Esophagus ,

The role of antioxidants in the pathogenesis of reflux esophagitis (RE), Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC) remains unknown. We evaluated the associations among dietary antioxidant intake and these diseases. We performed an assessment of dietary antioxidant intake in a case control study of RE (n = 219), BE (n = 220), EAC (n = 224), and matched population controls (n = 256) (the Factors Influencing the Barrett’s Adenocarcinoma Relationship study) using a modification of a validated FFQ. We found that overall antioxidant index, a measure of the combined intake of vitamin C, vitamin E, total carotenoids, and selenium, was associated with a reduced risk of EAC [odds ratio (OR) = 0.57; 95% CI = 0.33–0.98], but not BE (OR = 0.95; 95% CI = 0.53–1.71) or RE (OR = 1.60; 95% CI = 0.86–2.98), for those in the highest compared with lowest category of intake. Those in the highest category of vitamin C intake had a lower risk of EAC (OR = 0.37; 95% CI = 0.21–0.66; P-trend = 0.001) and RE (OR = 0.46; 95% CI = 0.24–0.90; P-trend = 0.03) compared with those in the lowest category. Vitamin C intake was not associated with BE, and intake of vitamin E, total carotenoids, zinc, copper, or selenium was not associated with EAC, BE, or RE. In conclusion, the overall antioxidant index was associated with a reduced risk of EAC. Higher dietary intake of vitamin C was associated with a reduced risk of EAC and RE. These results suggest that antioxidants may play a role in the pathogenesis of RE and EAC and may be more important in terms of progression rather than initiation of the disease process.

Bringing GERD Management up to PAR-2

Proton pump inhibitors (PPIs) are extremely effective for mucosal healing of reflux esophagitis, but less so for relieving the symptom of heartburn. PPIs block the secretion of gastric acid, the caustic effects of which have been assumed to be the primary culprit in the pathogenesis of reflux esophagitis. However, mounting data suggest that reflux-stimulated, immune-mediated mechanisms may underlie the development of esophagitis in patients with gastroesophageal reflux disease (GERD). Thus, the future of GERD therapy, particularly for patients who are refractory to PPIs, may be the targeting of proteins such as proteinase-activated receptor-2, which have central roles in the generation of immune-mediated esophageal mucosal damage and in eliciting the symptom of heartburn.

Immunohistochemical analysis of Ki-67, p53 and Bcl-2 expression related to histological features in gastroesophageal reflux disease

The endoscopic and histologic findings of gastroesophageal reflux disease are usually indistinct. The current study was designed to define accurately the histology in gastroesophageal reflux disease and to develop a hypothesis that reflux produces immunohistochemical changes. The study was based on the examination of endoscopic esophageal biopsy specimens obtained from 20 patients with evidence of reflux with 24-hour pH-meter monitoring and from 20 control subjects without clinical or endoscopic reflux. The pathogenesis of reflux esophagitis was discussed by comparing the histopathologic changes with determined Ki-67, p53 and Bcl-2 immunoreactivity. In this study, the presence of esophagitis was determined endoscopically in only 55% of the patients with gastroesophageal reflux disease, while microscopic esophagitis was detected in 60% of them. No correlation was found between presence of endoscopic esophagitis and microscopic esophagitis in the patients with gastroesophageal reflux disease. There was a significant difference between control cases and the patients according to histological parameters, which included basal activity (p=0.006), height of papillae (p=0.006), intraepithelial neutrophils (p=0.000), intraepithelial eosinophils (p=0.006), congestion (p=0.001), and dilated intercellular spaces (p=0.006). Immunohistochemically, there was a significant difference in the expression of p53 and Ki-67 between the three study groups (patients with/without microscopic esophagitis, controls) (p<0.05). However, there was no difference in Bcl-2 between the patients with reflux and control cases. In this study, we considered that microscopic esophagitis does not always accompany reflux, and the lack of reliable diagnostic histologic criteria is still a serious problem for pathologists. Immunohistochemically, an increase in cell proliferative activity and p53 protein accumulation to repair oxidative DNA damage related to reflux were observed. However, the close Bcl-2 immunoreactivity in all groups that was indicated by a weak positivity suggests that the inhibition of apoptosis may not be involved in reflux esophagitis.

The role of acid and bile reflux in oesophagitis and Barrett's metaplasia

The precise mechanisms whereby gastro-oesophageal reflux disease causes reflux oesophagitis and Barrett's oesophagus are not clear, even though these diseases have been known to be linked for many years. Recent studies indicate a role for the reflux-induced inflammatory response of oesophageal squamous epithelial cells and the immune cells in the pathogenesis of reflux oesophagitis. Although reflux oesophagitis commonly heals with oesophageal squamous cell regeneration, in some individuals the oesophagus heals through the process of metaplasia, a condition termed Barrett's oesophagus. Recent studies indicate that individual differences in the reflux-mediated response of oesophageal squamous epithelial cells in the type of immune response and/or in signalling pathways that regulate cell proliferation or cell phenotype may determine whether the oesophagus heals with the regeneration of squamous cells or through Barrett's metaplasia.

Surgical treatment of Gastroesophageal Reflux disease: yesterday and today

Gastroesophageal reflux disease (GERD) is a set of signs and symptoms and changes resulting from pathological backward flow of gastric or intestinal contents to the esophagus. Reflux of gastric contents occurs periodically in all people during a 24-hour period. Therefore physiological reflux of gastric contents that does not cause any complaints or histopathological changes in the esophagus should be differentiated from gastroesophageal reflux disease that results in subjective complaints or its complications confirmed by diagnostic methods. Prevalence of gastroesophageal reflux disease is difficult to estimate, however it is believed to occur in 0.35 to 2% of the whole population (1). Before a decision is taken to proceed with surgical treatment, detailed diagnostic workup of causes of pathological gastroesophageal reflux is required and the strategy of surgical treatment should be based on three basic principles: alleviation of typical subjective complaints, healing and prevention of recurrences of reflux injury of the esophageal mucosa and prevention of possible complications of the long standing disease such as bleeding, ulceration and esophageal stricture, aspiration pneumonia and intestinal metaplasia. Approach of surgeons to pathogenesis of esophageal ulcerations changed since Quincke reported for the first time three cases of this condition in 1879. Quincke concluded that similar macroscopic nature of esophageal ulcers and gastric ulcers and close anatomical proximity indicated that reflux of gastric juice into the esophagus could be the cause of “ulcer ex digestion”. In 1906 Tileston presented a similar concept, on the basis of examination of 41 cases of esophageal ulcerations, supporting his concept with Albert’s publications from 1839. In 1946 Allison presented a new disease entity – “peptic oesophagitis”. He reported it on the basis of clinical signs and symptoms and radiographic picture. He concluded that abnormal reflux of gastric juice through abnormal cardia is a pathological factor of the new disease. However Barret in 1950 suggested a new term for the disease reported by Allison – reflux esophagitis that was to reflect relationship between esophagitis and the disease etiological factor. A paper published in 1988 allowed us to understand a role of individual anatomical factors of so called anti-reflux mechanism, protecting against pathological gastroesophageal reflux. Further progress in the understanding of gastroesophageal reflux was associated with development of diagnostic methods used to diagnose gastroesophageal reflux and its consequences. In 1926 Robin and Jankelson were the first to demonstrate gastroesophageal reflux using a radiological study (2-8). Detailed assessment of gastroesophageal reflux and development of knowledge about pathogenesis of reflux esophagitis facilitated progress in implementation of new methods of surgical treatment of this disease. In 1919 Soeresi was the first to perform an operation

Bile and acid reflux in the pathogenesis of reflux oesophagitis in children

The aim of this study was to investigate the role of bile and acid reflux in the pathogenesis of reflux oesophagitis (RE) in children. A total of 44 patients aged 5-17 years with gastro-oesophageal reflux symptoms were enrolled. Simultaneous 24-h oesophageal Bilitec 2000 (Medtronic Instruments, Minneapolis, MN, USA) bilirubin monitoring and pH monitoring, in biopsy of oesophageal mucosa by gastro-endoscopy, were performed in all patients. According to the diagnostic criteria of pathological acid reflux and pathological bile reflux, 10 of 44 cases (22.7%) had acid reflux, 10 (22.7%) had isolated bile reflux, 16 (36.4%) had mixed acid and bile reflux, and the other eight (18.2%) had no reflux. Significant difference was observed in the ratio of different patterns of reflux between the RE group (26 cases) and the non-erosive reflux disease (NERD) group (18 cases) (chi(2) = 9.096, P < 0.01). All the parameters of acid reflux in the RE group were higher significantly than that in the NERD group (P < 0.05 or P < 0.01). A total of 20 out of 26 cases (76.9%) with RE had oesophageal acid reflux as against six out of 18 cases (33.3%) in patients with NERD (P < 0.01). The difference of each parameter of bile reflux had not reached significance between the two groups. Mixed reflux is the predominant form of reflux in the causation of oesophageal mucosal injury in children. Isolated bile reflux also plays a role in the development of RE, although only in patients without acid reflux.

American Gastroenterological Association Institute Technical Review on the Management of Gastroesophageal Reflux Disease

American Gastroenterological Association Institute Technical Review on the Management of Gastroesophageal Reflux Disease

Reactive oxygen species and chemokines: Are they elevated in the esophageal mucosa of children with gastroesophageal reflux disease?

To determine the role of inflammatory cytokines and reactive oxygen species (ROS) in childhood reflux esophagitis. A total of 59 subjects who had complaints suggesting GERD underwent esophagogastroduodenoscopy. Endoscopic and histopathologic diagnosis of reflux esophagitis was established by Savary-Miller and Vandenplas grading systems, respectively. Esophageal biopsy specimens were taken from the esophagus 20% proximal above the esophagogastric junction for conventional histopathological examination and the measurements of ROS and cytokine levels. ROS were measured by chemiluminescence, whereas IL-8 and MCP-1 levels were determined with quantitative immunometric ELISA on esophageal tissue. Esophageal tissue ROS, IL-8 and MCP-1 levels were compared among groups with and without endoscopic/histo-pathologic esophagitis. Of 59 patients 28 (47.5%) had normal esophagus whereas 31 (52.5%) had endoscopic esophagitis. In histopathological evaluation, almost 73% of the cases had mild and 6.8% had moderate degree of esophagitis. When ROS and chemokine levels were compared among groups with and without endoscopic esophagitis, statistical difference could not be found between patients with and without esophagitis. Although the levels of ROS, IL-8 and MCP-1 were found to be higher in the group with histopathological reflux esophagitis, this difference was not statistically significant. These results suggest that the grade of esophagitis is usually mild or moderate during childhood and factors apart from ROS, IL-8 and MCP-1 may be involved in the pathogenesis of reflux esophagitis in children.